Project Summary/Abstract Nitrogen is the fourth most common element in pharmaceuticals and biologically active molecules, after only C, H and O. Its incidence greatly eclipses that of other important elements such as S and F. Methods to introduce nitrogen moieties into commonly available starting materials would provide practitioners with rapid access to more complex structures. We have had a long-standing interest in assembling nitrogen heterocycles due to their prevalence and importance. Our work began with approaches to construction of bicyclic structures using cycloaddition chemistry. Over time, it evolved to using C?H activation and generating monocyclic structures. With an eye towards increased utility and impact, we have continued to evolve our approach to using increasingly abundant alkene partners with broadly versatile amine derivatives for the continued synthesis of nitrogen heterocycles as well as acyclic scaffolds. Thus, this competitive renewal is focused on several complementary venues: Aim 1: Stereospecific Catalytic Alkene Difunctionalization Reactions. Alkenes are among the most ubiquitous starting materials available. The delivery of two functionalities across the stereochemically defined alkene allows access to complementary diastereomers if the reaction is stereospecific. We will develop a suite of difunctionalization reactions including carboamination, carbocarbation and related transformations. Where possible we will use unfunctionalized precursors in such a way to increase utility and ease of execution. Aim 2: Chemoselective Coupling of Alkenes and Nitrogen Electrophiles. We will extend alkene functionalization chemistry to convert simple ?-olefins directly into pyrrolidines, piperidines and allylic amine derivatives, functionalizing not just the alkene itself but also the allylic, homoallylic and bis-homoallylic positions. Aim 3: Design of Artificial Metalloenzymes for Enhanced Reactivity and Asymmetric Catalysis. Many of these reactions create chiral products. We will control the absolute stereochemistry of the transformations with novel metalloenzymes derived from transition metal catalysts docked within monomeric streptavidin protein scaffolds.